title: Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity.
abstract: p53, a critical tumor suppressor, regulates mitochondrial respiration, but how a nuclear protein can orchestrate the function of an organelle encoded by two separate genomes, both of which require p53 for their integrity, remains unclear. Here we report that the mammalian homolog of the yeast mitochondrial disulfide relay protein Mia40 (CHCHD4) is necessary for the respiratory-dependent translocation of p53 into the mitochondria. In the setting of oxidative stress, increased CHCHD4 expression partitions p53 into the mitochondria and protects its genomic integrity while decreasing p53 nuclear localization and transcriptional activity. Conversely, decreased CHCHD4 expression prevents the mitochondrial translocation of p53 while augmenting its nuclear localization and activity. Thus, the mitochondrial disulfide relay system allows p53 to regulate two spatially segregated genomes depending on oxidative metabolic activity.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhuang
authors.forename: Ping-yuan
authors.initials: PY
authors.lastname: Wang
authors.forename: Xinglu
authors.initials: X
authors.lastname: Huang
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Ju-Gyeong
authors.initials: JG
authors.lastname: Kang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hwang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C507282:CHCHD4 protein, human; D004272:DNA, Mitochondrial; D004220:Disulfides; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D016159:Tumor Suppressor Protein p53
keywords: DNA repair; mitochondrial DNA; mutant p53